Process for preparing a 5-hydroxy-3-oxo-hexanoic acid derivative

ABSTRACT

The present invention is related to a novel process for preparing an optically active 5-hydroxy-3-oxo-hexanoic acid derivative or its tautomer which is useful intermediate for preparing statins such as atorvastatin and rosuvastatin. Blaise reaction of (S)-4-halo-3-hydroxybutyronitrile with -haloacetate is utilized as a key reaction to provide the product with minimal formation of side products and in good yield.

TECHNICAL FIELD

The present invention is related to a novel process for preparing anoptically active 5-hydroxy-3-oxo-hexanoic acid derivative of thefollowing formula (1):

or its tautomer, in which

-   R represents hydrogen, saturated-C₁–C₄-alkyl, or    unsaturated-C₂–C₄-alkyl, and-   X represents halogen such as Br, Cl, I, etc., which is a useful    intermediate for preparing statins such as atorvastatin,    rosuvastatin, etc. known as an agent for the treatment of    hypercholesterolemia and hyperlipidemia.

BACKGROUND ART

In the existing process for preparing the above compound of formula (1),an optically active 3-hydroxyester compound was reacted with lithiumenolate of t-butylacetate generated by the treatment of lithiumdiisopropylamide (LDA) or lithium hexamethyldisilazide (LHMDS) at lowtemperature (−78° C.) to provide compound of formula (1) (see: U.S. Pat.No. 5,278,313). Recently, a similar reaction to the above wassuccessfully carried out by the addition of Grignard reagent beforeClaisen condensation. This condition enabled the reaction performed at5° C. (see: European Patent Laid-open Publication No. 1104750).

The above processes, however, used excess lithium hexamethyldisilazideor lithium diisopropylamide that has some problems to be used in theindustrial production. Moreover, the former route is complicated by theformation of significant amount of undesired side products even at verylow temperature (see: Tetraehdron Lett., 2002, 43, 2679–2682). Thelatter precedent results in pretty low yield comparing to the formerprocess. The only advantage of the latter process is that the reactioncan be executed at 5° C.

DISCLOSURE OF THE INVENTION

The present inventors have conducted extensive researches to overcomethe above problems of the existing processes. As a result, the inventorshave developed a novel process for preparing the compound of formula (1)by Blaise reaction of (S)-4-halo-3-hydroxybutyronitrile andα-haloacetate using zinc metal activated in situ by an organic acid orits derivative. This novel route resulted in the formation of sideproducts to a minimal quantity and all the reactions are executed ataround ambient temperature or above.

Therefore, the present invention provides an effective process forpreparing the compound of formula (1), as defined above, or its tautomerusing Blaise reaction which uses zinc metal activated in situ by anorganic acid or its derivative.

BEST MODE FOR CARRYING OUT THE INVENTION

The present invention is related to a process for preparing the compoundof formula (1):

or its tautomer, in which

-   R represents hydrogen, saturated-C₁–C₄-alkyl, or    unsaturated-C₂–C₄-alkyl, and-   X represents halogen such as Br, Cl, I, etc., which comprises the    following steps:-   1) (S)-4-halo-3-hydroxybutyronitile derivative of the following    formula (2)

in which

-   X is as defined as above, and-   P represents hydrogen or a hydroxy-protecting group, is reacted with    an α-haloacetate compound of the following formula (3)    YCH₂CO₂R   (3)    in which-   R is as defined above, and-   Y represents Br or I, in the presence of zinc metal activated by an    organic acid or its derivative in an organic solvent and-   2) the product of step 1) is hydrolyzed in the presence of aqueous    acid solution.

The tautomer of the compound of formula (1) means the enol form compoundof the following formula (1a):

However, the compound of formula (1) is obtained as the main product ofthe process according to the present invention.

The key feature of the present invention is that the nitrilefunctionality of formula (2) is subjected to Blaise reaction ofα-haloacetate of formula (3) using zinc metal activated by an organicacid or its derivative to introduce the β-ketoester group of formula(1). The reaction mechanism can be depicted as the following ReactionScheme 1:

In the process of the present invention, to a stirred suspension of zincmetal in organic solvent is added catalytic amount of an organic acid orits derivative and the mixture is stirred under reflux to activate thezinc metal. To the mixture are added slowly the nitrile compound offormula (2) and the α-haloacetate compound of formula (3) in order toprepare the enamine intermediate of formula (4). After the completion ofthe reaction, the whole mixture is hydrolyzed by aqueous acid solutionto provide the desired compound of formula (1). The respective reactionconditions will be explained in more detail below.

The group P in formula (2) represents hydrogen or a hydroxy-protectinggroup. The hydroxy-protecting group includes SiRR¹R² wherein R is asdefined above, and R¹ and R² each represent hydrogen,saturated-C₁–C₆-alkyl, unsaturated-C₂–C₆-alkyl, or C₆–C₁₂-aromaticgroup, and ethoxyethyl, and tetrahydropyranyl. The group SiRR¹R²preferably includes trimethylsilyl (TMS), triethylsilyl (TES),t-butyldimethylsilyl (TBDMS), and t-butyldiphenylsilyl (TBDPS).Trimethylsilyl is the most preferable as the hydroxy-protecting group inthe aspect of purity and yield.

As reaction solvent, tetrahydrofuran, benzene, toluene and ether may beused. Among them, tetrahydrofuran is the most preferable in terms ofpurity and yield.

The α-haloacetate compound of formula (3) is added dropwise over 0.5 to2.0 hours, and the purity and yield are the most satisfactory when theaddition time is between 1.0 and 1.5 hour. It is preferable to use thecompound of formula (3) in an amount of 1.0 to 3.0 equiv with respect tothe compound of formula (2). Particularly, it is good to use thecompound of formula (3) wherein R is saturated-C₁–C₄-alkyl. Among thealkyl-haloacetate, isopropyl-haloacetate is better than methyl- orethyl-haloacetate, and t-butyl-haloacetate is better thanisopropyl-haloacetate in terms of yield.

The zinc metal is preferably used in an amount of 1.0 to 3.0 equiv withrespect to the compound of formula (2). The zinc metal is usuallystirred with solvent under reflux at a temperature ranging from 20 to120° C. It is preferable to use zinc dust or zinc powder.

As an organic acid or its derivative for activating the zinc metal, itis preferable to use R³CO₂H, R³SO₃H, R³CO₂TMS, R³SO₃TMS, or (R³SO₂)₂NHwherein R³ represents hydrogen, saturated-C₁–C₆-alkyl,unsaturated-C₂–C₆-alkyl, saturated-C₁–C₆-alkyl substituted by halogen,unsaturated-C₂–C₆-alkyl substituted by halogen, C₆–C₁₂-aromatic orC₆–C₁₂-aromatic substituted by halogen in 0.001 to 0.1 equiv withrespect to the compound of formula (2).

Aqueous hydrochloric acid or sulfuric acid may be used in the hydrolysisreaction step and hydrochloric acid is more suitable. It is preferableto adjust the pH of the reaction solution to 3 to 4 in the aspect ofpurity and yield. The aqueous acid solution is added dropwise at atemperature ranging from 0 to 5° C., and it is preferable to be stirredfor hydrolysis at the same temperature.

The process according to the present invention provides advantages overthe known precedents: 1) side products formation is minimized, 2) allthe reactions are executed at around ambient temperature or above, 3)minimal use of reagents, α-haloacetate compound and zinc, isaccomplished by employing the organic acid mediated activation.

All these improvements should lead to efficient execution of theprocess, and increased quality and yield of the product.

The present invention will be more specifically explained by thefollowing example.

EXAMPLES Example 1 Preparation of (S)-6-chloro-5-hydroxy-3-oxo-hexanoicacid t-butylester

Zinc dust (690 mg), tetrahydrofuran (4.0 mL), and methanesulfonic acid(10 mg) were introduced into a reaction vessel and the mixture wasstirred under reflux. To the mixture was added(S)-4-chloro-3-trimethylsilanyloxybutyronitrile (1.00 g) andsubsequently t-butylbromoacetate (2.04 g) over 1 hour. The mixture wasstirred under reflux for 30 minutes, and cooled to 0° C. Aqueous 3 Nhydrochloric acid solution was added dropwise until the acidity of thereaction solution became pH 4, and the reaction solution was stirred for3 hours. After the completion of reaction, tetrahydrofuran was distilledoff under reduced pressure, and the residue was extracted with ethylacetate and purified by silica gel column chromatography (eluent: ethylacetate/n-hexane=⅓, v/v) to give the title compound in a yield of 87%(1.07 g).

¹H NMR (400 MHz, CDCl₃)δ

Enol form (7%): 12.40 (bs, 1H), 5.01 (s, 1H), 4.19 (m, 1H), 3.61 (m,2H), 2.88 (m, 2H), 2.54 (m, 1H), 2.49 (bs, 1H), 2.47 (m, 1H), 1.49 (s,9H).

Keto Form (93%): 4.32 (m, 1H), 3.62 (m, 2H), 3.42 (s, 2H), 3.00 (bd,1H), 2.8 (m, 2H), 1.48 (s, 9H).

Mass (ESI, m/z): 497 (2M+Na+2), 495 (2M+Na), 261 (M+Na+2), 259 (M+Na).

1. A process for preparing a compound of formula (1)

or its tautomer, in which R represents hydrogen, saturated-C₁–C₄-alkyl,or unsaturated-C₂–C₄-alkyl, and X represents halogen, which comprisesthe following steps: 1) (S)-4-halo-3-hydroxybutyronitrile derivative ofthe following formula (2)

in which X is as defined above, and P represents hydrogen or ahydroxy-protecting group, is reacted with an α-haloacetate compound ofthe following formula (3)YCH₂CO₂R   (3) in which R is as defined above, and Y represents Br or I,in the presence of zinc metal activated by an organic acid or itsderivative in an organic solvent and 2) the product of step 1) ishydrolyzed in the presence of aqueous acid solution.
 2. The process ofclaim 1 wherein P of the (S)-4halo-3-hydroxybutyronitrile derivative offormula (2) represents hydrogen, or represents SiRR¹R² wherein R is asdefined in claim 1, and R¹ and R² each represent hydrogen,saturated-C₁–C₆-alkyl, unsaturated-C₂–C₆-alkyl, or C₆–C₁₂-aromaticgroup, or represents ethoxyethyl or tetrahydropyranyl.
 3. The process ofclaim 2 wherein P represents trimethylsilyl, triethylsilyl,t-butyldimethylsilyl, or t-butyldiphenylsilyl.
 4. The process of claim 3wherein P represents trimethylsilyl.
 5. The process of claim 1 whereinthe organic solvent is one or more selected from a group consisting oftetrahydrofuran, benzene, toluene, and ether.
 6. The process of claim 5wherein the organic solvent is tetrahydrofuran.
 7. The process of claim1 wherein R of the α-haloacetate compound of formula (3) representssaturated-C₁–C₄-alkyl.
 8. The process of claim 7 wherein R representst-butyl.
 9. The process of claim 1 or 7 wherein the α-haloacetatecompound of formula (3) is used in an amount of 1.0 to 3.0 equiv withrespect to the compound of formula (2).
 10. The process of claim 1wherein the zinc metal is used in an amount of 1.0 to 3.0 equiv withrespect to the compound of formula (2).
 11. The process of claim 10wherein the zinc metal is zinc dust or zinc powder.
 12. The process ofclaim 1 wherein the organic acid or its derivative is selected from agroup consisting of R³CO₂H, R³SO₃H, R³CO₂TMS, R³SO₃TMS, and (R³SO₂)₂NHwherein R³ represents hydrogen, saturated-C₁–C₆-alkyl,unsaturated-C₂–C₆-alkyl, saturated-C₁–C₆-alkyl substituted by halogen,unsaturated-C₂–C₆-alkyl substituted by halogen, C₆–C₁₂-aromatic, orC₆–C₁₂-aromatic substituted by halogen.
 13. The process of claim 12wherein the organic acid or its derivative is used in an amount of 0.001to 0.1 equiv with respect to the compound of formula (2).
 14. Theprocess of claim 1 wherein the aqueous acid solution is aqueoushydrochloric or sulfuric acid solution.
 15. The process of claim 1wherein the aqueous acid solution is added in an amount to adjust the pHto 3˜4.
 16. The process of claim 15 wherein the aqueous acid solution isadded dropwise at a temperature ranging from 0 to 5° C.